Currently in its 10th year of funding, this P01's objective is to achieve durable growth control in multiple myeloma (MM) through highly integrated translational research conducted by clinical and basic scientists. The overall hypothesis will be pursued that various components of the bone marrow microenvironment (ME) contribute to eventual treatment failure by providing (in a MM genotype-specific manner) a plethora of survival and proliferation signals, and that novel therapeutic strategies, coincapacitating MM and ME, will augment growth control. Through a combination of autotransplantsupported high-dose melphalan and therapies that co-target MM and ME, therapeutic strategies will be employed to maximize sustained complete responses. Novel immunotherapeutic approaches are aimed at augmenting autologous host responses via cancer/testis antigen vaccination and employing allogeneic natural killer cells and cytotoxic T lymphocytes. Gene expression profiling (GEP) should improve prognostic models and identify, in concert with Project 4, genes involved in pathogenetic cross talk between MM and ME. Because soluble syndecan-1 has cytokine-trapping properties, studies will determine if blocking heparan sulfate function or its bioavailability may inhibit tumor growth and dissemination. To successfully implement these Projects, 4 Cores are required: A) Admin., Data Mgmt., and Biostatistics; B) Functional Imaging; C) Molecular Genetics; and D) Cell Analysis/Tissue Banking. With access to a large patient population with MM, treated in a hypothesis-driven clinical trial setting with comprehensive follow-up, this P01 will shed light on the molecular and biological mechanisms of disease development/ progression and the current obstacles to sustaining complete remission.